CuET promotes cuproptosis and ferroptosis of lung cancer cells by interacting directly with polyunsaturated phospholipids.

The FDA-approved disulfiram (DSF) is metabolized to diethyldithiocarbamate-copper (CuET) in vivo, exhibiting excellent anti-tumor activity in various types of tumors. Although cuproptosis and ferroptosis are both reported to be involved in the tumor-killing effects of CuET, the specific crosstalk mechanism remains poorly understood. Herein, we found that CuET increased the concentration of copper ions significantly in non-small cell lung cancer (NSCLC) cells, thereby triggering the process of cuproptosis. Simultaneously, we observed an increase in lipid peroxidation (LPO) and ferroptosis. Mechanistically, CuET interacts directly with polyunsaturated phospholipids to generate free radicals, leading to LPO and ferroptosis, with limited dependence on iron accumulation. Additionally, lipid composition changes induced by CuET might also contribute to ferroptosis. In vivo anti-tumor experiments verified copper-mediated cell death. We uncovered that CuET induced ferroptosis through a copper-triggered, non-canonical, and radical-dependent pathway. Therefore, our data elucidate a therapeutic approach for NSCLC by co-targeting cuproptosis and ferroptosis.